Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fluoxetine is a potent and specific inhibitor of 5-HT uptake even after prolonged dosing. Both fluoxetine and norfluoxetine, an active metabolite, have a long plasma half life. The drug is extensively metabolized and undergoes renal elimination. Impairment of renal function, increasing age or obesity do not appear to alter the disposition of fluoxetine, although hepatic impairment predictably decreases the clearance of the drug. Recent data suggests that fluoxetine is an inhibitor of cytochrome P450-II-D6 in man and has been shown to inhibit the metabolism of a number of drugs which are substrates for this isoenzyme. It does not, however, affect the elimination of ethanol and does not enhance the effect of ethanol on psychometric testing. Fluoxetine has no effect on normal blood pressure although mean heart rate is slightly reduced. It does not appear to have a clinically significant effect on pituitary function. Although there is psychometric and EEG evidence to suggest a vigilance enhancing property, fluoxetine does not exhibit stimulant activity of the amphetamine type and has been shown to be well tolerated at doses clinically useful for appetite suppression in extensive clinical trials and widespread clinical use since marketed in 1987 for depressive illness.
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PMID:The human pharmacology of fluoxetine. 133 86

Rats, neonatally treated with monosodium aspartate (MSA), exhibited developmental defects through adulthood that were characterized by stunted growth, obesity, and reduced size of the liver, kidney, adrenals, and pituitary. Adult male and female rats treated with 4 mg of MSA had no detectable plasma growth hormone as determined from serial blood samples taken every 15 min for 8 consecutive hr. Associated with this loss of circulating growth hormone in the males was a dramatic decline in in vivo and in vitro hexobarbital metabolism and hepatic cytochrome P450 to female levels. The loss of plasma growth hormone in the females had no effect on the already low levels of hepatic monooxygenases. At 2 mg/g body weight, MSA produced both sex- and dose-dependent effects that were far more subtle than the full-blown obesity and growth retardation associated with the larger 4-mg dose. While the mean concentration of circulating growth hormone was reduced 70 to 90% in 2-mg-MSA-treated rats, the sexually dimorphic, ultradian patterns of growth hormone secretion were undisturbed. Affected males continued to secrete a pulse of growth hormone every 3 hr, albeit at greatly reduced amplitudes, interposed by normally undetectable baselines. Similarly, 2-mg-MSA-treated females had greatly reduced mean levels of plasma growth hormone, but with the usual secretion of multiple pulses never dropping to baseline. Surprisingly, the sex-dependent, hepatic monooxygenases, which are normally regulated by the ultradian secretions of growth hormone, were unaffected by the 2-mg MSA treatment. Our results suggest that while an ultradian pulse of circulating growth hormone is necessary for the characteristically male profile of hepatic monooxygenases, neither the amplitude of the secretory peaks nor their total growth hormone content is critical.
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PMID:Sex- and dose-dependent effects of neonatally administered aspartate on the ultradian patterns of circulating growth hormone regulating hexobarbital metabolism and action. 167 77

Changes in the components of hepatic microsomal electron transport systems and in drug hydroxylase activities were investigated in ventromedial hypothalamus (VMH) lesioned obese rats. Eight weeks after electrolysis of the bilateral VMH, the content of cytochrome P450 per mg microsomal protein (0.79 +/- 0.07 nmol/mg protein) was significantly higher (P less than 0.02) than that in the sham-operated rats (0.59 +/- 0.02). Cytochrome P450 per whole liver in the VMH-lesioned obese rats had also significantly increased (87 +/- 9 nmol vs 56 +/- 3, P less than 0.02). No significant differences were found in the cytochrome b5 contents, and the activities of NADPH- and NADH-cytochrome c reductases between the VMH-lesioned obese and sham-operated rats. The demethylation activities of aminopyrine (1.04 +/- 0.02 nmol/mg protein/min vs 0.94 +/- 0.02, P less than 0.05) and p-nitroanisole (0.96 +/- 0.02 vs 0.89 +/- 0.02 , p less than 0.02) and the aniline hydroxylase activity (0.22 +/- 0.01 vs 0.16 +/- 0.01, P less than 0.01) were enhanced, but 7-ethoxycoumarin O-deethylase activity was unchanged in the VMH-lesioned obese rats. These results indicate a selective increase in the content of cytochrome P450 among the components of the P450-dependent mixed function oxidase system in the liver of VMH-lesioned obese rats. Our observations suggest that drug metabolism may be enhanced in the hypothalamic obesity.
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PMID:Selective increase in cytochrome P450 content in hepatic microsomes from rats with ventromedial hypothalamic lesions. 204 15

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.
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PMID:Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus. 250 Oct 61

Neonatal male rats were treated with monosodium glutamate (MSG) at either 2 or 4 mg/g BW on alternate days during the first 10 days of life. As adults, the 4 mg MSG-treated rats displayed the obesity, growth retardation, and reduced pituitary weights that typify this syndrome. These animals had no detectable plasma GH as determined from serial blood samples taken every 20 min for 8 consecutive h. Associated with this loss of circulating GH was an induction of the female-specific hepatic cytochrome P450 2d (gene IIC12) and the disappearance of the male-specific form of cytochrome P450 2c (gene IIC11). The catalytic activities of cytochrome P450 2c (i.e. androgen 16 alpha- and 2 alpha-hydroxylase), sex-dependent hexobarbital hydroxylase and total cytochrome P450 were similarly feminized. Rats exposed to the 2-mg dose of MSG were also obese, but their growth rates and pituitary sizes were not as severely affected as in the 4 mg MSG-treated rats. Circulating GH in these lower dosed males was secreted in a pulsatile pattern similar to that in normal males, except that the pulse amplitude was reduced as much as 90%. In spite of this profound decline in GH peak heights in the 2 mg MSG-treated males, liver metabolism was characteristically masculine. That is, female-specific cytochrome P450 2d remained undetectable, while the male forms of cytochrome P450 2c, 2a (gene IIIA2), and RLM2 (gene IIA2), their respective catalytic steroid hydroxylase activities, and associated sex-dependent drug-metabolizing enzymes were expressed at the level of or greater than that in normal males. Thus, while an ultradian pulse of circulating GH is necessary for the characteristically masculine profile of sex-specific forms of hepatic cytochrome P450, neither the amplitude of the secretory peaks nor their total GH content is critical, and these can be greatly reduced from the normal male levels.
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PMID:Signalling elements in the ultradian rhythm of circulating growth hormone regulating expression of sex-dependent forms of hepatic cytochrome P450. 251 Sep 88

We aim to evaluate the effects of phenobarbital (PB) on the liver drug metabolism, NADPH production capacity and terminal gluconeogenic enzyme, glucose-6-phosphatase (G6Pase) activity in the diabetic state associated with genetic obesity in mice. The results showed that PB treatment increased the amount of liver total cytochrome P450 (cytP450), a drug metabolizing monooxygenase enzyme in genetically obese, hyperglycemic (ob/ob) mice 6-fold and the total activities of other monooxygenase enzymes NADPH cytP450 reductase and 7-ethoxyresorufin O-deethylase (ERDE) 2- and 6.5-fold, respectively. In addition, the regimen increased the liver total activities of two NADPH generating enzymes, 6-phosphogluconate dehydrogenase (6PGDH) and malic enzyme (ME) in obese mice suggesting that the regimen enhanced liver NADPH production capacity in the animals. The data further showed that PB treatment decreased the high hepatic G6Pase activity in obese mice. Both enhanced NADPH generating enzyme activities and lowered G6Pase activity may suppress hepatic glucose output. Since NADPH is required for drug oxidation reactions as a reducing cofactor, high NADPH generating capacity may facilitate liver drug metabolism in vivo. Although the diabetic state in obese mice differs somewhat from that seen in non-insulin dependent diabetic subjects (NIDDs), these findings provide some knowledge about the possible biochemical mechanisms whereby PB treatment normalizes drug metabolism and glycemic control in NIDDs, as has been noted in previous studies.
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PMID:Hepatic drug metabolism and the activities of NADPH generating enzymes and glucose-6-phosphatase in phenobarbital treated genetically obese (ob/ob) mice. 283 24

In this study, the overfed rat was employed as a model for examining the influence of obesity on the regulation of hepatic cytochromes P450 3A and 2C11 (CYP3A and CYP2C11, respectively). These proteins represent the predominant constitutive hepatic P450 enzymes of male rats. Sprague-Dawley rats were chronically fed a standard pelleted diet or an energy-dense diet which typically results in significant increases in body weight, serum triglyceride levels and liver lipid content. Obesity did not influence baseline levels of spectral cytochrome P450 content. Similar baseline activities of CYP3A (testosterone 6 beta-hydroxylation), comparative CYP3A protein levels (Western blot) and steady-state CYP3A mRNA (slot blot), were found in rats fed either diet. Likewise, obesity did not appear to influence CYP2C11 at the enzyme activity (testosterone 2 alpha-hydroxylation) or mRNA levels. Half of the animals in each group received 20 mg phenobarbital (intraperitoneal injection) per animal every 12 hours for three consecutive days. This resulted in similar phenobarbital plasma concentrations in both groups. Phenobarbital treatment increased the concentrations of total cytochrome P450 in both lean and obese rats to the same extent. CYP3A activity, protein and mRNA levels were induced to a similar magnitude in rats fed either diet. Furthermore, obesity did not influence CYP2C11 activity or mRNA levels following administration of phenobarbital. A lack of an effect of obesity and the altered lipid environment on the regulation of CYP3A and CYP2C11 is in contrast to other enzymes studied previously. It is apparent that the consequences of obesity on hepatic cytochrome P450 may be enzyme-specific.
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PMID:Expression of the CYP3A and CYP2C11 enzymes in a nutritionally obese rodent model: response to phenobarbital treatment. 808 27

The present study determined the effect of genetic obesity and phenobarbital (PB) treatment on the expression and regulation of the hepatic cytochrome P450 enzyme (CYP2C11) in Fa/? and fa/fa Zucker rats. Hepatic CYP2C11 levels as determined by Western immunoblotting and associated enzymatic activity (testosterone oxidation at the 2 alpha position) were significantly lower in untreated fa/fa Zucker rats compared with that observed in Fa/? Zucker rats. There was no significant difference in the constitutive CYP2C11 steady-state mRNA level hybridizable to the cDNA (P450 16 alpha) or specific oligonucleotide probe (Northern and slot blot analyses) between fa/fa and Fa/? Zucker rats. The depressed constitutive CYP2C11 protein levels in fa/fa rats may be attributed to their low plasma testosterone and growth hormone levels; however, lack of differences in CYP2C11 steady-state mRNA suggest post-transcriptional regulatory mechanism(s). Treatment with PB further suppressed hepatic CYP2C11 protein levels and activities in both fa/fa and Fa/? Zucker rats in comparison with that seen in controls. The level of CYP2C11 steady-state mRNA was significantly higher after treatment with PB in Fa/? Zucker rats, while no change was observed in fa/fa animals. The mechanism by which PB treatment fails to increase CYP2C11 steady-state mRNA levels in the fa/fa Zucker rat is unknown; however, it may share a common molecular basis with the defect in nuclear transcription rate previously observed with CYP2B1/2B2.
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PMID:Expression of a male-specific cytochrome P450 isozyme (CYP2C11) in fa/fa Zucker rats: effect of phenobarbital treatment. 827 26

Neonatal exposure to monosodium glutamate (MSG) permanently blocks growth hormone (GH) secretion, which results in the development of a well-defined syndrome characterized by stunted body growth, obesity and impaired drug metabolism. We have found that restoration of the normal masculine circulating profile of GH (i.e., six daily pulses) by use of an external pumping apparatus is ineffective in restoring the normal expression of hepatic cytochrome P450 2C11, a major GH-dependent drug and steroid metabolizing enzyme that is eliminated by MSG treatment. Moreover, administering GH at two, four or seven plasma pulses per day with amplitudes ranging from physiologic to 7 times normal were similarly ineffective in restoring the expression (at both an activity and mRNA level) of the cytochrome. Additionally, multicytochrome P450-dependent hexobarbital hydroxylase was also unresponsive to GH administration in the MSG-treated rats. Because GH replacement was unable to correct the enzyme defects, our results suggest that the developmental abnormalities produced by neonatal MSG are not simply a result of a GH deficiency per se, but are due to an irreversible insensitivity of the target cell to GH.
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PMID:Irreversible suppression of growth hormone-dependent cytochrome P450 2C11 in adult rats neonatally treated with monosodium glutamate. 849 38

Perfluorooctanoic acid (PFOA) produces marked hepatic effects, including hepatomegaly, focal hepatocyte necrosis, hypolipidemia, and alteration of hepatic lipid metabolism in a number of animal species. In rodents, PFOA is a peroxisome proliferator, an inducer of members of the cytochrome P450 superfamily and other enzymes involved in xenobiotic metabolism, an uncoupler of oxidative phosphorylation, and may not be a cancer promoter. Although PFOA is the major organofluorine compound found in humans, little information is available concerning human responses to PFOA exposure. This study of 115 occupationally exposed workers examined the cross-sectional associations between PFOA and hepatic enzymes, lipoproteins, and cholesterol. The findings indicate that there is no significant clinical hepatic toxicity at the PFOA levels observed in this study. PFOA may modulate the previously described hepatic responses to obesity and xenobiotics.
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PMID:Serum perfluorooctanoic acid and hepatic enzymes, lipoproteins, and cholesterol: a study of occupationally exposed men. 873 32


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